Research

Unrelated Hematopoietic Cell Transplantation in a Patient with Combined Immunodeficiency with Granulomatous Disease and Autoimmunity Secondary to RAG Deficiency.

J Clin Immunol. 2016 Aug 18;

Authors: John T, Walter JE, Schuetz C, Chen K, Abraham RS, Bonfim C, Boyce TG, Joshi AY, Kang E, Carvalho BT, Mahajerin A, Nugent D, Puthenveetil G, Soni A, Su H, Cowan MJ, Notarangelo L, Buchbinder D

Abstract
The use of HLA-identical hematopoietic stem cell transplantation (HSCT) demonstrates overall survival rates greater than 75 % for T-B-NK+ severe combined immunodeficiency secondary to pathogenic mutation of recombinase activating genes 1 and 2 (RAG1/2). Limited data exist regarding the use of HSCT in patients with hypomorphic RAG variants marked by greater preservation of RAG activity and associated phenotypes such as granulomatous disease in combination with autoimmunity. We describe a 17-year-old with combined immunodeficiency and immune dysregulation characterized by granulomatous lung disease and autoimmunity secondary to compound heterozygous RAG mutations. A myeloablative reduced toxicity HSCT was completed using an unrelated bone marrow donor. With the increasing cases of immune dysregulation being discovered with hypomorphic RAG variants, the use of HSCT may advance to the forefront of treatment. This case serves to discuss indications of HSCT, approaches to preparative therapy, and the potential complications in this growing cohort of patients with immune dysregulation and RAG deficiency.

PMID: 27539235 [PubMed – as supplied by publisher]

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Mutations in pyrin masquerading as a primary immunodeficiency.

Clin Immunol. 2016 Aug 15;

Authors: Badran YR, Rajab M, Hanna-Wakim R, Bainter W, Cangemi B, Massaad MJ, Dbaibo G, Geha RS, Chou J

Abstract
Whole exome sequencing is increasingly used in the diagnosis of primary immunodeficiencies due to the overlapping and atypical presentations of these disorders. We report two patients who presented with recurrent infections and early onset colitis. They were investigated by whole exome sequencing due to suspicion of primary immunodeficiency and found to have mutations in pyrin known to cause familial Mediterranean fever.

PMID: 27538774 [PubMed – as supplied by publisher]

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Establishing and characterizing a new primary effusion lymphoma cell line harboring Kaposi’s sarcoma-associated herpesvirus.

Infect Agent Cancer. 2016;11:37

Authors: Osawa M, Mine S, Ota S, Kato K, Sekizuka T, Kuroda M, Kataoka M, Fukumoto H, Sato Y, Kanno T, Hasegawa H, Ueda K, Fukayama M, Maeda T, Kanoh S, Kawana A, Fujikura Y, Katano H

Abstract
BACKGROUND: Primary effusion lymphoma is a rare distinct large B-cell neoplasm that is associated with Kaposi’s sarcoma-associated herpesvirus (KSHV) infection. Over recent years, 9 KSHV-positive/Epstein-Barr virus (EBV)-negative PEL cell lines have been established.
METHODS: Tumor cells were collected from the pleural effusion of a 49-year-old male with AIDS. Cells were grown in RPMI1640 culture medium supplemented with 10 % fetus bovine serum. Single cell cloning was performed successfully by a limiting dilution method in a 96-well plate. The cell line obtained was designated SPEL.
RESULTS: SPEL cells showed gourd-shaped morphology with a polarized nucleus, expressing CD38, CD138, and Blimp-1, but not B cell markers such as CD19 and CD20. Polymerase chain reaction analysis revealed that SPEL cells were positive for KSHV but negative for EBV. Tetradecanoylphorbol acetate induced expression of KSHV lytic proteins and the production of KSHV particles in SPEL cells. Subcutaneous inoculation of SPEL cells into severe combined immunodeficiency mice resulted in the formation of solid tumors. Next-generation sequencing revealed the 138 kbp genome sequence of KSHV in SPEL cells. Suberic bishydroxamate, a histone deacetylase inhibitor, induced the expression of KSHV-encoded lytic proteins and cell death in SPEL cells.
CONCLUSIONS: A new KSHV-positive and EBV-negative PEL cell line, SPEL was established. This cell line may contribute to furthering our understanding of the pathogenesis of PEL and KSHV infection.

PMID: 27536332 [PubMed]

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Increased PI3K/Akt activity and deregulated humoral immune response in human PTEN deficiency.

J Allergy Clin Immunol. 2016 Aug 13;

Authors: Driessen GJ, IJspeert H, Wentink M, Yntema HG, van Hagen PM, van Strien A, Bucciol G, Cogulu O, Trip M, Nillesen W, Peeters EA, Pico-Knijnenburg I, Barendregt BH, Rizzi M, van Dongen JJ, Kutukculer N, van der Burg M

Abstract
PTEN deficiency in humans is associated with PTEN Hamartoma Tumor Syndromes (PHTS). It causes increased activation of the PI3K/Akt pathway and we here show that the humoral immune response is deregulated resulting in CSR and SHM deficiency. This is clinically apparent in part of the PHTS patients as antibody deficiency. In conclusion, PI3K/Akt signaling is important for the human B-cell response to antigens and deregulated signaling is implicated in the pathophysiology of antibody deficiency.

PMID: 27531073 [PubMed – as supplied by publisher]

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Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorder Presenting as Primary Bone Lymphoma in a Patient with Rheumatoid Arthritis.

Intern Med. 2016;55(16):2259-64

Authors: Ishiguro K, Hayashi T, Aoki Y, Murakami R, Ikeda H, Ishida T

Abstract
Primary bone lymphoma (PBL) is a rare disorder. We herein present a case of other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD) presenting as PBL. A 63-year-old woman was diagnosed with rheumatoid arthritis and had been treated with methotrexate for seven years. Two months before admission, she suffered from pain in the limbs. Magnetic resonance imaging revealed multiple irregular lesions in the bones of the limbs, which showed an uptake of (18)F-FDG on positron emission tomography. A biopsy of the right radius revealed diffuse large B-cell lymphoma, leading to the diagnosis of OIIA-LPD. She received rituximab-containing regimens resulting in a complete response.

PMID: 27523005 [PubMed – in process]

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Amyloidosis as a Renal Complication of Chronic Granulomatous Disease.

Iran J Kidney Dis. 2016 Jul;10(4):228-32

Authors: Darougar S, Rashid Farokhi F, Tajik S, Baghaie N, Amirmoini M, Bashardoust B, Hashemitari SK, Mahdaviani SA

Abstract
Chronic granulomatous disease is a rare primary immunodeficiency disorder, which leads to increased susceptibility to recurrent infections and severe inflammatory manifestations.  There have been reports regarding different aspects of genitourinary involvement in chronic granulomatous disease, some of which are hydronephrosis, granulomatous cystitis, and glomerulonephritis, but among these complications, amyloidosis is rather rare. We report a patient with chronic granulomatous disease that developed amyloidosis later in the course of the disease.

PMID: 27514771 [PubMed – in process]

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Exclusion of Patients with a Severe T-Cell Defect Improves the Definition of Common Variable Immunodeficiency.

J Allergy Clin Immunol Pract. 2016 Aug 10;

Authors: Bertinchamp R, Gérard L, Boutboul D, Malphettes M, Fieschi C, Oksenhendler E, DEFI study group

Abstract
BACKGROUND: In 2014, the European Society for Immune Deficiencies (ESID) revised the common variable immunodeficiency (CVID) diagnosis criteria by incorporating new clinical and biological markers. The new definition appeared more restrictive but had not yet been evaluated in a large cohort of patients.
OBJECTIVE: The objective of this study was to evaluate the impact of this new definition in a large cohort of patients with primary hypogammaglobulinemia.
METHODS: Evaluation of 3 different CVID definitions (ESID/Pan-American Group for Immunodeficiency [PAGID] 1999, ESID 2014, DEFI 2015) in 521 patients included in the French DEFI study with a diagnosis of primary hypogammaglobulinemia.
RESULTS: Using the ESID/PAGID 1999 definition, 351 patients were classified as CVID. The new ESID 2014 definition excluded 62 (18%) patients. Most of them (n = 56; 90%) had a less severe disease, whereas 6 (10%) presented with a severe disease with major T-cell defect. We propose different criteria (occurrence of opportunistic infection or very low naive CD4+ T-cell count) to define this population with severe T-cell defect. Sixty-two patients fulfilled these criteria, represented 20% of the initial CVID population but accounted for 77% of the deaths, with a 5-year overall survival of 67.6% (95% confidence interval, 51.0-79.6), and were considered as late onset combined immunodeficiency (LOCID).
CONCLUSIONS: The new ESID definition for CVID still fails to exclude a large number of patients with severe T-cell defect. We propose a new definition (DEFI 2015) that excluded more patients with a T-cell defect and consider these patients as LOCID. This population has a poor outcome and should be considered as a distinct group requiring specific care.

PMID: 27522107 [PubMed – as supplied by publisher]

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